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- PDB-8dvb: Estrogen Receptor Alpha Ligand Binding Domain in Complex with (1'... -

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Basic information

Entry
Database: PDB / ID: 8dvb
TitleEstrogen Receptor Alpha Ligand Binding Domain in Complex with (1'-(4-((1-butylpyrrolidin-3-yl)methoxy)phenyl)-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl)(phenyl)methanone
ComponentsEstrogen receptor
KeywordsTRANSCRIPTION / Antiestrogen / breast cancer / alpha helical bundle / estrogen receptor
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / nuclear estrogen receptor activity / epithelial cell development / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / nuclear estrogen receptor activity / epithelial cell development / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / mammary gland branching involved in pregnancy / uterus development / negative regulation of smooth muscle cell apoptotic process / vagina development / TFIIB-class transcription factor binding / androgen metabolic process / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / Mitochondrial unfolded protein response (UPRmt) / nuclear receptor-mediated steroid hormone signaling pathway / positive regulation of DNA-binding transcription factor activity / negative regulation of DNA-binding transcription factor activity / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / positive regulation of nitric-oxide synthase activity / estrogen receptor signaling pathway / protein localization to chromatin / steroid binding / 14-3-3 protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / negative regulation of canonical NF-kappaB signal transduction / ESR-mediated signaling / TBP-class protein binding / negative regulation of miRNA transcription / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / transcription corepressor binding / transcription coregulator binding / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / transcription coactivator binding / male gonad development / nuclear receptor activity / positive regulation of fibroblast proliferation / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / response to estradiol / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / DNA-binding transcription activator activity, RNA polymerase II-specific / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / transcription regulator complex / Estrogen-dependent gene expression / DNA-binding transcription factor activity, RNA polymerase II-specific / calmodulin binding / Extra-nuclear estrogen signaling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling / DNA-binding transcription factor activity / negative regulation of gene expression / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / protein kinase binding / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / Golgi apparatus / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding / nucleus / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / Estrogen receptor/oestrogen-related receptor / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor ...Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / Estrogen receptor/oestrogen-related receptor / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-TZI / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsHancock, G.R. / Young, K.S. / Hosfield, D.J. / Joiner, C. / Sullivan, E.A. / Yildz, Y. / Laine, M. / Greene, G.L. / Fanning, S.W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: NPJ Breast Cancer / Year: 2022
Title: Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells.
Authors: Hancock, G.R. / Young, K.S. / Hosfield, D.J. / Joiner, C. / Sullivan, E.A. / Yildiz, Y. / Laine, M. / Greene, G.L. / Fanning, S.W.
History
DepositionJul 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 29, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,0954
Polymers58,0662
Non-polymers1,0292
Water2,468137
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2980 Å2
ΔGint-13 kcal/mol
Surface area19660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.096, 56.335, 87.348
Angle α, β, γ (deg.)90.00, 103.25, 90.00
Int Tables number5
Space group name H-MC121
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 29033.018 Da / Num. of mol.: 2 / Mutation: C381S, C417S, C530S, L536S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03372
#2: Chemical ChemComp-TZI / [(1'R)-1'-(4-{[(3R)-1-(3-fluoropropyl)pyrrolidin-3-yl]methoxy}phenyl)-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone


Mass: 514.630 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H35FN2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.31 Å3/Da / Density % sol: 42.15 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: PEG 3,350, MgCl2, HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 19241 / % possible obs: 99 % / Redundancy: 3.7 % / Biso Wilson estimate: 29.96 Å2 / CC1/2: 0.99 / Net I/σ(I): 25260
Reflection shellResolution: 2.19→2.3 Å / Num. unique obs: 5012 / CC1/2: 0.52

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
HKL-3000data reduction
HKL-3000data scaling
HKL-3000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5UFX

5ufx


Resolution: 2.19→49.12 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 27.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2421 965 5.02 %
Rwork0.192 --
obs0.1945 19241 75.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.19→49.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3634 0 76 137 3847
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043834
X-RAY DIFFRACTIONf_angle_d0.8315205
X-RAY DIFFRACTIONf_dihedral_angle_d14.868518
X-RAY DIFFRACTIONf_chiral_restr0.097611
X-RAY DIFFRACTIONf_plane_restr0.005641
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.19-2.30.3453590.24251277X-RAY DIFFRACTION37
2.3-2.450.30431150.23071742X-RAY DIFFRACTION51
2.45-2.640.30231230.22582204X-RAY DIFFRACTION65
2.64-2.90.29021440.23222751X-RAY DIFFRACTION81
2.9-3.320.29621680.2123331X-RAY DIFFRACTION96
3.32-4.190.18791710.17353459X-RAY DIFFRACTION100
4.19-49.120.21341850.16923512X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.98510.3357-0.58345.2326-0.81134.04040.16470.31410.2870.29830.17330.4194-0.3438-0.1628-0.27940.27710.077-0.07980.1386-0.03260.2185-4.40512.84325.469
23.54340.445-0.55011.1039-0.00043.9982-0.0330.1413-0.09690.04060.021-0.05160.0368-0.1646-0.01570.14730.03830.00870.1603-0.01470.2071-0.4715.3423.269
32.35350.5247-0.19251.85-1.93075.4622-0.0304-0.15960.02320.0783-0.06030.1384-0.03530.37240.05010.12910.0666-0.02760.1719-0.01650.1829.7627.45925.984
43.23130.17520.27051.3105-0.39862.9058-0.09410.37360.1162-0.1831-0.03150.05160.013-0.14490.14190.20740.03930.0170.2317-0.00440.221510.4098.67618.063
52.8780.3932.09727.78354.06377.0423-0.39380.4727-0.1334-0.08180.2997-0.3836-0.56610.1884-0.17550.2905-0.0443-0.05890.28390.08920.448439.8986.87331.675
63.1101-0.3431-0.32014.06552.81755.4434-0.02350.4194-0.5170.1610.1269-0.18020.55630.2977-0.15090.21510.04030.00240.2769-0.02580.343233.267-14.15822.998
72.1713-0.6440.73833.1493-0.1953.42420.24310.7379-0.1939-0.281-0.25840.169-0.1349-0.47910.07540.1920.11810.00290.3606-0.0430.247127.046-9.65817.631
82.99960.00351.91315.14491.34894.6781-0.0170.03880.1838-0.2144-0.25290.0513-0.12770.03150.21440.17710.11330.00720.34810.02470.24225.344-0.21119.428
93.95080.90320.86265.43010.42292.0732-0.1096-0.07060.32570.03510.08150.062-0.16450.06690.01050.14410.04370.02710.26580.03080.169125.0286.92924.521
105.21262.15630.67889.02692.15992.0536-0.12160.2607-0.03980.7213-0.3020.1196-0.2109-0.37480.33390.3489-0.02040.04440.39780.06460.216225.909-16.52234.593
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 307:341 )A307 - 341
2X-RAY DIFFRACTION2( CHAIN A AND RESID 342:420 )A342 - 420
3X-RAY DIFFRACTION3( CHAIN A AND RESID 421:465 )A421 - 465
4X-RAY DIFFRACTION4( CHAIN A AND RESID 466:550 )A466 - 550
5X-RAY DIFFRACTION5( CHAIN B AND RESID 307:321 )B307 - 321
6X-RAY DIFFRACTION6( CHAIN B AND RESID 322:371 )B322 - 371
7X-RAY DIFFRACTION7( CHAIN B AND RESID 372:420 )B372 - 420
8X-RAY DIFFRACTION8( CHAIN B AND RESID 421:461 )B421 - 461
9X-RAY DIFFRACTION9( CHAIN B AND RESID 470:525 )B470 - 525
10X-RAY DIFFRACTION10( CHAIN B AND RESID 526:545 )B526 - 545

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